Topological characterization of the mitochondrial phospholipid scramblase 3

Luévano‐Martínez, Luis Alberto; Kowaltowski, Alicia J.

doi:10.1002/1873-3468.12917

Cited by 7 publications

(4 citation statements)

References 55 publications

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“…How PLSCR3 could move cardiolipin from one of the leaflets in the inner mitochondrial membrane to one of the leaflets in the outer mitochondrial membrane remains unknown and has been questioned. 56 Gene ablation and structural studies have failed to provide a clear picture of the biological function of the PLSCR family of proteins. Plscr1 germline knockout mice exhibited no obvious phenotypic abnormality.…”

Section: Discussionmentioning

confidence: 99%

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Genome-Wide CRISPR Screen Identifies Phospholipid Scramblase 3 as the Biological Target of Mitoprotective Drug SS-31

Silvaroli,

Bisunke,

Kim

et al. 2024

JASN

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Background: The synthetic tetra-peptide SS-31 shows promise in alleviating mitochondrial dysfunction associated with common diseases. However, the precise pharmacological basis of its mitoprotective effects remains unknown. Methods: To uncover the biological targets of SS-31, we performed a genome-scale CRISPR screen in HK-2 cells, a cell culture model where SS-31 mitigates cisplatin-associated cell death and mitochondrial dysfunction. The identified hit candidate gene was functionally validated using knockout cell lines, siRNA mediated downregulation, and tubular epithelial specific conditional knockout mice. Biochemical interaction studies were also performed to examine the interaction of SS-31 with the identified target protein. Results: Our primary screen and validation studies in HK-2 and primary murine tubular epithelial cells showed that phospholipid scramblase 3 (PLSCR3), an understudied inner mitochondrial membrane protein, is essential for the protective effects of SS-31. For in vivo validation, we generated tubular epithelial-specific knockout mice and found that Plscr3 gene ablation did not influence kidney function under normal conditions or affect the severity of cisplatin and rhabdomyolysis-associated AKI. However, Plscr3 gene deletion completely abrogated the protective effects of SS-31 during cisplatin and rhabdomyolysis-associated AKI. Biochemical studies showed that SS-31 directly binds to a previously uncharacterized N-terminal domain and stimulates PLSCR3 scramblase activity. Finally, PLSCR3 protein expression was found to be increased in the kidneys of AKI patients. Conclusions: PLSCR3 is identified as the essential biological target that facilitates the mitoprotective effects of SS-31 in vitro and in vivo. PLSCR3 agonists can alleviate mitochondrial dysfunction linked to AKI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-Wide CRISPR Screen Identifies Phospholipid Scramblase 3 as the Biological Target of Mitoprotective Drug SS-31

Silvaroli,

Bisunke,

Kim

et al. 2024

JASN

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“…To gain insight into Scramb1 role in SD formation, we conducted structure-function studies. Most PLSCRs consist of an unstructured, poorly conserved, N-terminal prolinerich domain of variable length, followed by a globular, 12-stranded β-barrel domain, with a C-terminal hydrophobic α-helix suggested to be buried within the β-barrel central cavity [30,54,55]. We found that the proline-rich region of Drosophila Scramb1-A probably mediates its interaction with Pyd.…”

Section: Scramb1 Role In Membrane Remodeling During Sd Formationmentioning

confidence: 80%

Phospholipid scramblase 1: an essential component of the nephrocyte slit diaphragm

Castillo-Mancho,

Atienza-Manuel,

Sarmiento-Jiménez

et al. 2024

Cell. Mol. Life Sci.

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Blood ultrafiltration in nephrons critically depends on specialized intercellular junctions between podocytes, named slit diaphragms (SDs). Here, by studying a homologous structure found in Drosophila nephrocytes, we identify the phospholipid scramblase Scramb1 as an essential component of the SD, uncovering a novel link between membrane dynamics and SD formation. In scramb1 mutants, SDs fail to form. Instead, the SD components Sticks and stones/nephrin, Polychaetoid/ZO-1, and the Src-kinase Src64B/Fyn associate in cortical foci lacking the key SD protein Dumbfounded/NEPH1. Scramb1 interaction with Polychaetoid/ZO-1 and Flotillin2, the presence of essential putative palmitoylation sites and its capacity to oligomerize, suggest a function in promoting SD assembly within lipid raft microdomains. Furthermore, Scramb1 interactors as well as its functional sensitivity to temperature, suggest an active involvement in membrane remodeling processes during SD assembly. Remarkably, putative Ca2+-binding sites in Scramb1 are essential for its activity raising the possibility that Ca2+ signaling may control the assembly of SDs by impacting on Scramb1 activity.

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“…For example, cardiolipin was shown to stimulate the GTPase activity of Drp1, thereby promoting mitochondrial fission 80 . Interestingly, our mitochondrial proteomics data indicates that Plscr3b 81 , which has been implicated in facilitating the transport of cardiolipin from the inner to the outer mitochondrial membrane, is upregulated during embryogenesis, making it an additional candidate for future functional studies.…”

Section: Discussionmentioning

confidence: 99%

Increase in ER-mitochondria contacts and mitochondrial fusion are hallmarks of mitochondrial activation during embryogenesis

Chugunova,

Keresztes,

Kobylinska

et al. 2024

Preprint

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SummaryMitochondrial ATP production is essential for development, yet the mechanisms underlying the continuous increase in mitochondrial activity during embryogenesis remain elusive. Using zebrafish as a model system for vertebrate development, we comprehensively profile mitochondrial activity, morphology, metabolome, proteome and phospho-proteome as well as respiratory chain enzymatic activity. Our data show that the increase in mitochondrial activity during embryogenesis does not require mitochondrial biogenesis, is not limited by metabolic substrates at early stages, and occurs without an increase in the abundance of respiratory chain complexes or theirin vitroactivity. Our analyses pinpoint a previously unexplored increase in mitochondrial-ER association during early stages in combination with changes in mitochondrial morphology at later stages as possible contributors to the rise in mitochondrial activity during embryogenesis. Overall, our systematic profiling of the molecular and morphological changes to mitochondria during embryogenesis provides a valuable resource for further studying mitochondrial function during embryogenesis.

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Topological characterization of the mitochondrial phospholipid scramblase 3

Cited by 7 publications

References 55 publications

Genome-Wide CRISPR Screen Identifies Phospholipid Scramblase 3 as the Biological Target of Mitoprotective Drug SS-31

Genome-Wide CRISPR Screen Identifies Phospholipid Scramblase 3 as the Biological Target of Mitoprotective Drug SS-31

Phospholipid scramblase 1: an essential component of the nephrocyte slit diaphragm

Increase in ER-mitochondria contacts and mitochondrial fusion are hallmarks of mitochondrial activation during embryogenesis

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